Immune to Brain Communication in Ageing and Disease

Sickness behaviour and transient microglial activation are beneficial for individuals with a normal, healthy CNS, but in the ageing or diseased brain the response to peripheral infection can be detrimental and increases the rate of cognitive decline. Aged rodents exhibit exaggerated sickness and prolonged neuroinflammation in response to systemic infection, measured by increased levels of the proinflammatory cytokine IL-ip and microglia with increased levels of CD11b, CD68, MHCII, F4/80 [42-44]. Older people who contract a bacterial or viral infection or experience trauma postoperatively, also show exaggerated neuroinflammatory responses and are prone to develop delirium, a condition which results in a severe short term cognitive decline and a long term decline in brain function [45-47]. One explanation for these observations is that the innate immune cells of the CNS, the microglia are primed by their microenvironment due to neuronal changes and/or presence of misfolded proteins, and have a lower threshold for activation to secondary stimuli, including systemic infection. Priming is a well described response in macrophages in vitro, where an initial treatment of interferons or growth factors (e.g. IFNy, GM-CSF, G-CSF) exacerbates their response to LPS [48]. Godbout’s research group was the first to demonstrate the presence of primed microglia in aged rodents and showed twofold greater induction and prolonged expression of IL-ip and IL-6 mRNA in the brain after intraperitoneal injection of LPS in 20-24 month-old mice vs. 3-6 months adults. These molecular and cellular changes were accompanied with increased immobility in the forced swim test measured 72 h post infection and increased levels of indoleamine 2,3-dioxygenase (IDO), suggesting increased level of depression. Microglia are at least partly responsible for these effects as isolation of microglia from young and aged mice showed increased transcripts of IL-1p, iNOS and IDO [49-51], although other cell types, such as astrocytes and endothelial cells cannot be excluded. Peripheral surgical wounding in mice also activates microglia and increases the levels of TNFa and IL-6 in the hippocampus of both 9 and 18 month-old mice, but age potentiates these effects. In this study a critical role for peripheral macrophages and their production of TNFa was thought to drive cognitive impairment following aseptic trauma [52]. To unravel the underlying mechanisms, L’Episcopo et al., treated young and aged mice with HCT1026, a NO-donating derivative of flurbiprofen followed by a single sublethal dose of LPS. HCT1026 efficiently reversed the age-dependent increase of microglial activation in response to LPS to levels measured in younger mice and prevented the progressive loss of dopaminergic neurons in aged mice [53], suggesting that microglial priming occurs in multiple brain regions. Further experimental evidence for primed microglia, comes from studies using mice with ongoing neurodegeneration, which produce higher and prolonged levels of cytokines (IL-1p, TNFa) after local or peripheral LPS treatment resulting in nonreversible neuronal dysfunction and death [28]. Systemic administration of LPS also affects amyloid beta and tau pathology; two well described neuropathological hallmarks of AD. Repeated dosing of LPS can cause the accumulation of Ap in both wild type and transgenic APP mice due to increased beta secretase activity [54,55], and treating mice transgenic for human Tau (i.e. P301L, Tg4510) with LPS can result in the increased phosphorylation and accumulation of Tau in neurons [56]. Interestingly, a recently identified genetic risk factor for AD, CD33, was increased only in aged mice, which was correlated with increased Ap beta load, cognitive impairment and ameliorated by treatment with ibuprofen, suggesting that systemic inflammation can modulate neuroinflammation and aggregation of misfolded proteins [57, 58]. Collectively these studies demonstrate that peripheral inflammation can increase the accumulation of two neuropathological hallmarks of AD, further strengthening the hypothesis that inflammation in involved in the underlying pathology.

 
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